FIG. 7.

Central role of mitochondrial H₂O₂ in Mn physiology and toxicity. The present results show that Mn dose-response involves a low-dose activation of respiration and SOD2 activity without associated toxicity whereas further increase in Mn inhibits respiration, oxidizes cell GSH and protein thiols, and causes cell death. Over this entire range, H₂O₂ increases as a function of Mn, suggesting that H₂O₂ has a signaling role at lower Mn concentrations and a toxic role at higher Mn concentration. Elucidation of the interactions of Mn-containing complexes (Mn-metal, Mn-protein, Mn-metabolite, dotted circles) with these central Mn-dependent mitochondrial reactions could considerably enhance understanding of related neuronal disease mechanisms. Abbreviations: Pr-SH, protein thiol; GSSG, glutathione disulfide; DMT, divalent metal transporter; GLNA, glutamine synthetase; GLUD, glutamiate dehydrogenase; ApoTF, apotransferrin; PD, Parkinson’s Disease; HD, Huntington’s Disease.